The long-term goal of this project is to simultaneously decrease treatment-related morbidity from unnecessary over-treatment of men with localized prostate cancer (PCa) while curing more men by minimizing under- treatment of men with higher risk PCa. In this proposal we aim to determine if tissue based gene expression classifiers (GEC) can be utilized to improve both cancer control and quality of life (QOL) in men with localized PCa. This goal will be carried out through three specific aims. In Aim 1 we will develop a universal risk score that combines genetic, clinical, and pathologic variables in a manner that is agnostic to which of the three commercially available GEC tests used. This will be done through assembling a large cohort of men with targeted MRI/ultrasound fusion biopsies of the same prostate tumor focus and analyzing individual tumors with each of the three tests. We will then develop a conversion method aligning each GEC score with a new universal score, and we will apply this to a cohort of 1000 men with newly diagnosed prostate cancer followed in our statewide prospective registry. This data will be utilized to validate our recently developed clinical- genomic risk grouping system, broadening it to incorporate all GEC tests, and focusing it on appropriate stratification of favorable risk prostate cancer potentially suitable for active surveillance. We hypothesize that the universal integrated clinical-genomic risk groups will provide improved discrimination compared to standard clinical categories and will expand the pool of active surveillance-eligible patients. In Aim 2 we will conduct the first ever prospective randomized trial of the clinical utility and clinical impact of GEC testing in favorable risk localized prostate cancer, leveraging two statewide collaboratives containing over 60 urology and radiation oncology practices. Patients will be randomized to standard clinical risk stratification +/- GEC testing in order to determine the impact of testing on treatment decisions (active surveillance versus radical treatment), cancer control, and QOL. We hypothesize that GEC testing will decrease the use of primary therapy and increase QOL at 3 years, while maintaining rates of grade reclassification and biochemical recurrence at the same time point. Aim 3 seeks to determine the clinical impact of GEC testing on treatment failure and patient-reported QOL in men at high risk of recurrence post-prostatectomy. This aim leverages the recently accrued G-MINOR trial that randomized approximately 350 men at high risk of failure after prostatectomy to clinical risk stratification +/- GEC testing to assess decision making based on GEC testing. By extending the follow-up of this trial, we will determine how GEC testing impacts long-term tumor control and QOL. We hypothesize that GEC use in higher risk patients will provide more accurate risk stratification and targeted treatment decisions, leading to improved cancer control and QOL. This work has the potential to personalize treatment decision- making for PCa patients based on their tumor?s biology, allowing some men to avoid costly and toxic over- treatment while also decreasing the burden of recurrent disease from inappropriate under-treatment.